The Absence of LPA2 Attenuates Tumor Formation in an Experimental Model of Colitis-Associated Cancer

Lin, Shibin; Wang, Dongsheng; Iyer, Smita S.; Ghaleb, Amr M.; Shim, Hyunsuk; Yang, Vincent W.; Chun, Jerold; Yun, C. Chris

doi:10.1053/j.gastro.2009.01.002

Cited by 116 publications

(142 citation statements)

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“…KLF5 has been implicated in Ras-mediated transformation, and intestine-specific deletion of Klf5 in adult mice resulted in distorted villus and crypt structures and defective barrier functions (48,49). Our previous study identifies KLF5 as a mediator of LPA 2 -mediated proliferation of colon cancer cells, and studies using LPA 2 -deficient mice demonstrate the correlation between LPA 2 and KLF5 expression in vivo (16,17,23). The salient finding of this study is that KLF5 is a transcription factor that regulates HIF-1␣ expression in cells treated with LPA.…”

Section: Discussionmentioning

confidence: 66%

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Regulation of Hypoxia-inducible Factor 1α (HIF-1α) by Lysophosphatidic Acid Is Dependent on Interplay between p53 and Krüppel-like Factor 5

Lee

Dang

et al. 2013

Journal of Biological Chemistry

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Section: Discussionmentioning

confidence: 66%

“…LPA 2 -deficient intestinal tumors show reduced expression levels of cyclooxygenase 2, ␤-catenin, and Krüppel-like factor 5 (KLF5) (16,17). It has been shown that LPA stimulates vascular endothelial growth factor (VEGF) expression, whereas transgenic expression of LPA 2 in mouse ovaries produces VEGF and urokinase-type plasminogen activator (18,19).…”

mentioning

confidence: 99%

Regulation of Hypoxia-inducible Factor 1α (HIF-1α) by Lysophosphatidic Acid Is Dependent on Interplay between p53 and Krüppel-like Factor 5

Lee

Dang

et al. 2013

Journal of Biological Chemistry

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“…There is also strong evidence from xenograft mouse models and transgenic mice that LPA 2 is more oncogenic compared with LPA 1 and LPA 3 (17,59). The compelling evidence for the implication of LPA 2 as an oncogene stems from recent studies by Yun and co-workers (18,60) who showed that LPA 2 -deficient mice were more resistant to intestinal tumorigenesis induced by colitis or by ApcMin mutation. However, the molecular mechanisms for the oncogenic activity of LPA 2 are not well understood.…”

Section: Discussionmentioning

confidence: 92%

Lysophosphatidic Acid Activates Lipogenic Pathways and de Novo Lipid Synthesis in Ovarian Cancer Cells

Mukherjee

Barbour

et al. 2012

Journal of Biological Chemistry

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Background: Mechanisms underlying the lipogenic phenotype of cancer cells are poorly understood. Results: Lysophosphatidic acid (LPA) via its receptor LPA 2 activates lipogenic pathways and de novo lipid synthesis in ovarian cancer cells. Conclusion: LPA is causally linked to the aberrant lipogenesis in cancer. Significance: This study offers a new strategy to inhibit lipid anabolism in a cancer cell-specific manner.

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“…Mouse model studies have revealed an important role for the ATX-LPA receptor axis in tumor progression as well as in other pathologies, ranging from inflammation to fibrosis (2,(12)(13)(14)(15)(16)(17)(18)(19)(20)(21). Accordingly, pharmacological inhibition of ATX is an attractive way to interfere with LPA signaling for therapeutic benefit.…”

Section: Discussionmentioning

confidence: 99%

“…Forced overexpression of ATX or individual LPA receptors promotes tumor progression in mouse models (13)(14)(15)(16), while LPA receptor deficiency protects from colon carcinogenesis (17). In addition to its role in cancer, ATX-LPA signaling has been implicated in lymphocyte homing and (chronic) inflammation (18), fibrotic diseases (19 and 20), and thrombosis (21).…”

mentioning

confidence: 99%

Boronic acid-based inhibitor of autotaxin reveals rapid turnover of LPA in the circulation

Albers

Dong

Meeteren

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Autotaxin (ATX) is a secreted nucleotide pyrophosphatase/ phosphodiesterase that functions as a lysophospholipase D to produce the lipid mediator lysophosphatidic acid (LPA), a mitogen, chemoattractant, and survival factor for many cell types. The ATX-LPA signaling axis has been implicated in angiogenesis, chronic inflammation, fibrotic diseases and tumor progression, making this system an attractive target for therapy. However, potent and selective nonlipid inhibitors of ATX are currently not available. By screening a chemical library, we have identified thiazolidinediones that selectively inhibit ATX-mediated LPA production both in vitro and in vivo. Inhibitor potency was approximately 100-fold increased (IC 50 ∼ 30 nM) after the incorporation of a boronic acid moiety, designed to target the active-site threonine (T210) in ATX. Intravenous injection of this inhibitor into mice resulted in a surprisingly rapid decrease in plasma LPA levels, indicating that turnover of LPA in the circulation is much more dynamic than previously appreciated. Thus, boronic acid-based small molecules hold promise as candidate drugs to target ATX.A utotaxin (ATX or NPP2) is a secreted nucleotide pyrophosphatase/phosphodiesterase (NPP) originally isolated as an autocrine motility factor from melanoma cells (1). ATX, a ∼120 kDa glycoprotein, is unique amongst the NPPs in that it functions as a lysophospholipase D (lysoPLD) that converts extracellular lysophosphatidylcholine (LPC) into the lipid mediator lysophosphatidic acid (LPA; mono-acyl-sn-glycero-3-phosphate) (2-5). LPA acts on specific G protein-coupled receptors and thereby stimulates the migration, proliferation, and survival of many cell types (6 and 7) (Fig. 1). ATX is produced by various tissues and is the major LPA-producing enzyme in the circulation. Newly produced LPA is subject to degradation by membranebound lipid phosphate phosphatases (LPPs) (8 and 9). However, little is known about the dynamic regulation of steady-state LPA levels in vivo.ATX is essential for vascular development (10 and 11) and is found overexpressed in various human cancers (12). Forced overexpression of ATX or individual LPA receptors promotes tumor progression in mouse models (13-16), while LPA receptor deficiency protects from colon carcinogenesis (17). In addition to its role in cancer, ATX-LPA signaling has been implicated in lymphocyte homing and (chronic) inflammation (18), fibrotic diseases (19 and 20), and thrombosis (21). Therefore, the ATX-LPA axis qualifies as an attractive target for therapies.Potent and selective ATX inhibitors are now needed as a starting point for the development of targeted anti-ATX/LPA therapy. Direct targeting of LPA receptors seems to be a less attractive strategy, since LPA acts on multiple receptors that show overlapping activities (2 and 6). Since the initial finding that ATX is subject to product inhibition by LPA and sphingosine 1-phosphate (S1P) (22), various synthetic phospho-and phosphonate lipids have been explored as ATX inhibitors (23-26). However, s...

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The Absence of LPA2 Attenuates Tumor Formation in an Experimental Model of Colitis-Associated Cancer

Cited by 116 publications

References 46 publications

Regulation of Hypoxia-inducible Factor 1α (HIF-1α) by Lysophosphatidic Acid Is Dependent on Interplay between p53 and Krüppel-like Factor 5

Regulation of Hypoxia-inducible Factor 1α (HIF-1α) by Lysophosphatidic Acid Is Dependent on Interplay between p53 and Krüppel-like Factor 5

Lysophosphatidic Acid Activates Lipogenic Pathways and de Novo Lipid Synthesis in Ovarian Cancer Cells

Boronic acid-based inhibitor of autotaxin reveals rapid turnover of LPA in the circulation

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